Efficient reconstruction of bone with high quality is critical for the success of dental implants, periodontal regeneration and treatments of bone defects in general. The goal of this study is to develop a means for efficient bone regeneration based on a unique function of a matrix proteoglycan in bone, biglycan (BGN). We have demonstrated that BGN accelerates osteoblast differentiation and matrix mineralization in vitro and that clones overexpressing BGN efficiently produced highly organized mineralized matrix upon their transplantation into immunodeficient mice. This function could be due in part to the unique ability of the BGN core protein to positively modulate the functions of specific bone morphogenetic proteins (BMPs). Based on these and other preliminary data, we hypothesized that the specific domain of BGN core protein, i.e. the effector domain, exerts this unique function and is capable of promoting the formation of bone with high quality in vivo. To test this hypothesis, two specific aims are proposed: in Aim 1, we will identify the effector domain by generating several BGN core protein-derived constructs and evaluating their capabilities to promote BMP-2 function, osteoblast differentiation and mineralization in vitro, and in Aim 2, we will test if the BGN/effector domain can promote bone formation in vivo employing a rat mandible defect model. The results of this study may provide insights into an effective, novel matrix-assisted bone formation and may help develop new therapeutic strategies for treating bone defects. PUBLIC HEALTH RELEVANCE: A growing population of our aging society is suffering from craniofacial bone defects. Given the severely impaired quality of life and limitations of current treatments, development of new therapeutic strategies is of critical importance. Towards this end, this study will explore a novel approach to efficient and cost-effective craniofacial bone regeneration based on a unique function of bone matrix molecule, biglycan.